OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity

Esther Hoste (), Kim Lecomte, Karl Annusver, Niels Vandamme, Jana Roels, Sophia Maschalidi, Lien Verboom, Hanna-Kaisa Vikkula, Mozes Sze, Lisette Van Hove, Kevin Verstaen, Arne Martens, Tino Hochepied, Yvan Saeys, Kodi Ravichandran, Maria Kasper and Geert van Loo ()
Additional contact information
Esther Hoste: VIB Center for Inflammation Research
Kim Lecomte: VIB Center for Inflammation Research
Karl Annusver: Karolinska Institutet
Niels Vandamme: VIB Center for Inflammation Research
Jana Roels: VIB Center for Inflammation Research
Sophia Maschalidi: VIB Center for Inflammation Research
Lien Verboom: VIB Center for Inflammation Research
Hanna-Kaisa Vikkula: VIB Center for Inflammation Research
Mozes Sze: VIB Center for Inflammation Research
Lisette Van Hove: VIB Center for Inflammation Research
Kevin Verstaen: VIB Center for Inflammation Research
Arne Martens: VIB Center for Inflammation Research
Tino Hochepied: VIB Center for Inflammation Research
Yvan Saeys: VIB Center for Inflammation Research
Kodi Ravichandran: VIB Center for Inflammation Research
Maria Kasper: Karolinska Institutet
Geert van Loo: VIB Center for Inflammation Research

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation of Otulin selectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion of Tnfr1, knockin expression of kinase-inactive Ripk1 or keratinocyte-specific deletion of Fadd and Mlkl completely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, thereby identifying keratinocyte cell death as the driving force for inflammation. Single-cell RNA-sequencing comparing non-lesional and lesional skin reveals changes in epidermal stem cell identity in OTULIN-deficient keratinocytes prior to substantial immune cell infiltration. Keratinocytes lacking OTULIN display a type-1 interferon and IL-1β response signature, and genetic or pharmacologic inhibition of these cytokines partially inhibits skin inflammation. Finally, expression of a hypomorphic mutant Otulin allele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25944-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25944-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25944-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().